Fulminant type 1 diabetes developed after influenza split vaccination

in Endocrinology, Diabetes & Metabolism Case Reports
Authors:
Toshitaka Sawamura Department of Internal Medicine, Asanogawa General Hospital, Kosakamachinaka, Kanazawa, Ishikawa, Japan
Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medicine, Takaramachi, Kanazawa, Japan
Department of Health Promotion and Medicine of the Future, Kanazawa University, Takaramachi, Kanazawa, Japan

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Shigehiro Karashima Department of Health Promotion and Medicine of the Future, Kanazawa University, Takaramachi, Kanazawa, Japan

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Ai Ohmori Department of Internal Medicine, Asanogawa General Hospital, Kosakamachinaka, Kanazawa, Ishikawa, Japan
Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medicine, Takaramachi, Kanazawa, Japan

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Kei Sawada Department of Internal Medicine, Asanogawa General Hospital, Kosakamachinaka, Kanazawa, Ishikawa, Japan

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Daisuke Aono Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medicine, Takaramachi, Kanazawa, Japan
Department of Health Promotion and Medicine of the Future, Kanazawa University, Takaramachi, Kanazawa, Japan

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Mitsuhiro Kometani Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medicine, Takaramachi, Kanazawa, Japan
Department of Health Promotion and Medicine of the Future, Kanazawa University, Takaramachi, Kanazawa, Japan

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Yoshiyu Takeda Department of Internal Medicine, Asanogawa General Hospital, Kosakamachinaka, Kanazawa, Ishikawa, Japan

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Takashi Yoneda Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medicine, Takaramachi, Kanazawa, Japan
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Correspondence should be addressed to T Sawamura; Email: sawaa1124@asanogawa-gh.or.jp
Open access

Summary

Fulminant type 1 diabetes (FT1D) is a subtype of diabetes characterized by rapid progression of β-cell destruction, hyperglycemia, and diabetic ketoacidosis (DKA). The pathogenesis of this disease remains unclear. However, viral infections, HLA genes, and immune checkpoint inhibitor use were reportedly involved in this disease. A 51-year-old Japanese man with no chronic medical condition was admitted to our hospital with complaints of nausea and vomiting. Cough, sore throat, nasal discharge, and diarrhea were not noted. He had a medical history of at least two influenza infections. His vaccination history was notable for receiving an inactive split influenza vaccine 12 days prior to developing these symptoms. He was diagnosed with DKA associated with FT1D. His HLA class II genotypes were nonsusceptible to FT1D, and he had a negative history of immune checkpoint inhibitor use. The destruction of the pancreas by cytotoxic T cells is reported to be involved in FT1D. Inactive split influenza vaccines do not directly activate cytotoxic T cells. However, these could activate the redifferentiation of memory CD8-positive T cells into cytotoxic T cells and induce FT1D, as this patient had a history of influenza infections.

Learning points

  • Influenza split vaccination could cause fulminant type 1 diabetes (FT1D).

  • The mechanism of influenza split vaccine-induced FT1D might be through the redifferentiation of CD8-positive memory T cells into cytotoxic T cells.

Abstract

Summary

Fulminant type 1 diabetes (FT1D) is a subtype of diabetes characterized by rapid progression of β-cell destruction, hyperglycemia, and diabetic ketoacidosis (DKA). The pathogenesis of this disease remains unclear. However, viral infections, HLA genes, and immune checkpoint inhibitor use were reportedly involved in this disease. A 51-year-old Japanese man with no chronic medical condition was admitted to our hospital with complaints of nausea and vomiting. Cough, sore throat, nasal discharge, and diarrhea were not noted. He had a medical history of at least two influenza infections. His vaccination history was notable for receiving an inactive split influenza vaccine 12 days prior to developing these symptoms. He was diagnosed with DKA associated with FT1D. His HLA class II genotypes were nonsusceptible to FT1D, and he had a negative history of immune checkpoint inhibitor use. The destruction of the pancreas by cytotoxic T cells is reported to be involved in FT1D. Inactive split influenza vaccines do not directly activate cytotoxic T cells. However, these could activate the redifferentiation of memory CD8-positive T cells into cytotoxic T cells and induce FT1D, as this patient had a history of influenza infections.

Learning points

  • Influenza split vaccination could cause fulminant type 1 diabetes (FT1D).

  • The mechanism of influenza split vaccine-induced FT1D might be through the redifferentiation of CD8-positive memory T cells into cytotoxic T cells.

Background

Fulminant type 1 diabetes (FT1D) is a subtype of type 1 diabetes characterized by rapid progression of β-cell destruction, hyperglycemia, and diabetic ketoacidosis (DKA) within a few days. The diagnostic criteria described by Imagawa et al. include the following: (1) rapid progression to DKA or ketosis, (2) plasma glucose level higher than 288 mg/dL, (3) hemoglobin A1c (HbA1c) level lower than 8.7%, and (4) fasting serum C-peptide level lower than 0.3 ng/mL with C-peptide level lower than 0.5 ng/mL after glucagon loading (1).

FT1D lacks the insulitis and hyperexpression of MCH class I in the islet cells. Compared with other types of type 1 diabetes, the onset that is dramatic and almost no β-cells remain at disease onset. In addition to β-cell, the destruction of α-cell and cellular infiltration in the exocrine tissue are also observed in FT1D. Cellular immunity is thought to be involved, and islet-related antibodies are usually negative. Moreover, HLA DRB1*0405-DQB1*0401 is reported as a susceptible haplotype (1, 2, 3).

It has been reported that the activation of autoimmunity as a history of viral infections, certain HLA polymorphisms, and an administration of immune checkpoint inhibitors contribute to the development of FT1D (2).

Here, we describe a case of FT1D developed after inactive split influenza vaccination, in the absence of classic triggers.

Case presentation

A 51-year-old Japanese man with no chronic medical conditions presented to our hospital with complaints of nausea and vomiting for 2 days. He complained of polyuria and polydipsia for 5 days prior to admission. Cough, sore throat, nasal discharge, and diarrhea were not noted. His medical history was notable for 2 prior influenza infections about 20 years ago and 5 years ago. His family history was unremarkable. Moreover, he did not have a cold, acute hepatitis, shingles, herpes infection, or diarrhea by rotavirus within one year. He was not taking any medications. His fasting plasma glucose level was 101 mg/dL, and his HbA1c level was 5.8% in the health check-up performed 40 days prior to admission. His vaccination history was notable for receiving an inactive split influenza vaccine 12 days prior to developing these symptoms. He had not received any other vaccines in the preceding year.

On admission, his body weight and BMI were 69.0 kg and 25.9 kg/m2, respectively. His body weight decreased 2.0 kg in past 1 week. He had a blood pressure of 101/70 mmHg, a heart rate of 133 beats/min, a temperature of 37.1 ℃, a oxygen saturation of 98% in room air, and a respiratory rate of 36 breaths/min. There were no abnormalities upon examining the chest and abdomen.

Investigation

As shown in Table 1, laboratory evaluation revealed high blood glucose level (779 mg/dL), metabolic acidosis, elevated serum total ketone level, mildly elevated HbA1c level (7.6%), and markedly elevated glycoalbumin level (37.4%). Moreover, an elevation in serum amylase level (215 mg/dL) was observed. Evaluation of C-peptide immunoreactivity indicated an insulin-insufficient state. He was diagnosed with DKA associated with FT1D. Anti-glutamic acid decarboxylase antibody, anti-insulinoma-associated antigen-2 antibody, islet cell antibody, and anti-zinc transporter 8 antibody were all negative. His HLA class II genotypes were DRB1*15:02-DQB1*06:01 and DRB1*04;06-DQB1*06:01, which are nonsusceptible to FT1D.

Table 1

Laboratory examination on admission.

Value Normal range
Blood
 WBC count, /μL 24 600 4800–10 800
 RBC count, × 106/μL  5.75 4.20–5.40
 Hemoglobin, g/dL 19.1 12.0–16.0
 Platelet count, × 103/μL 292 130–400
 AST, U/L  16 13–33
 ALT, U/L  32 6–222
 Total bilirubin, mg/dL  0.8 0.4–1.2
 Amylase, mg/dL 215 37–124
 Total protein, g/dL  7.4 6.7–8.3
 Albumin, g/dL  4.7 3.8–5.2
 Sodium, mEq/L 129 135–149
 Potassium, mEq/L  5.5 3.5–4.9
 Chloride, mEq/L  88 96–108
 BUN, mg/dL  46 8.0–22.0
 Creatinine, mg/dL 1.72 0.50–0.80
 CRP, mg/dL 0.23 <0.3
 Glucose, mg/dL 779 69–140
 HbA1c, %  7.6 4.6–6.2
 GA, % 37.4 12.4–16.3
 CPR, ng/mL  0.26 0.8–2.5
 Total ketone body, μmol/L 8443 26–122
 Acetoacelate, μmol/L 2681 13–69
 3-Hydroxybutyrate, μmol/L 5762 0–76
 GAD antibody Negative Negative
 IA-2 antibody Negative Negative
 ICA antibody Negative Negative
 ZnT8 zntibody Negative Negative
Urine
 Specific gravity 1.037 1.005–1.030
 Glucose 4+ Negative
 Protein Negative Negative
 Ketone body 4+ Negative
 Urine C-peptide, μg/day 2.3 29.2–167.0
Arterial blood gas
 PH 7.189 7.38–7.46
 pCO2, mmHg  15.7 32.0–46.0
 pO2, mmHg 136.7 74.0–108.0
 HCO3, mEq/L  5.8 21.0–29.0
 BE, mEq/L −19.2 −2 to 2

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BE, base excess; BUN, blood urea nitrogen; CPR, C-peptide immunoreactivity; CRP, C-reactive protein; GA, glycoalbumin; GAD, anti-glutamic acid decarboxylase; HbA1c, hemoglobin A1c; IA-2, Insulinoma-associated antigen-2; IC, islet cell; pH, potential hydrogen; RBC, red blood cell; WBC, white blood cell; ZnT8, zinc transporter 8.

Treatment

Intravenous insulin and saline infusions were administered, leading to an improvement in his symptoms, blood glucose level, and metabolic acidosis. After 2 days of i.v. insulin therapy, he was started on a diet with s.c. multiple daily injections (MDI), which included insulin glargine U300 and insulin lispro. The course of blood glucose levels, serum amylase levels, and C-peptide immunoreactivity is described in Table 2. Finally, the patient was discharged with an insulin daily total dose of 46 units, which were 0.66 units/kg at day 15. His body weight returned to 71.2 kg at the time of discharge.

Table 2

The course of insulin secretion and blood parameters.

Health check-up On admission Day 3 Day 7 Day 14 6 Months
Amylase, U/L N/A 215 176 74 56 63
CPR, ng/mL N/A 0.26 <0.03 N/A <0.03 <0.03
BG, mg/dL 101 779 131 124 111 105
HbA1c, % 5.8 7.6 N/A N/A N/A 7.4
A/G ratio 1.41 1.74 1.74 1.37 1.45 1.33

A/G ratio, albumin to globulin ratio; BG, blood glucose level; CPR, C-peptide immunoreactivity; HbA1c, hemoglobin A1c.

Outcome and follow-up

After his discharge, treatment with multiple daily injection (MDI) and diet therapy was continued. Six months after his discharge, his HbA1c level was 7.4% and his total daily insulin dose was 40 units.

Discussion

This was a case of FT1D developed after inactive split influenza vaccination.

Shibasaki et al. reported the expression of Toll-like receptor-7 (TLR-7) and cytotoxic T cells invasion in the pancreas, in the autopsies of patients with FT1D (4). Moreover, Chujo et al. revealed that CD8-positive cytotoxic T cells were more common in patients with FT1D than in patients with other type 1 diabetes by an integrated assay using peripheral blood mononuclear cells (5). Therefore, cytotoxic T cells-induced destruction of the pancreas is the most plausible mechanism of FT1D.

Sano et al. reported the first case of FT1D after influenza B virus infection (6). The patient had no remarkable medical and family histories. Moreover, the HLA gene genotype of this patient was DRB1*0405-DQB1*0401. FT1D was developed 6 days after the influenza B virus infection. Although the trigger is different and the HLA gene genotype is susceptible to FT1D, this case is comparable to our case in terms of the onset time from the trigger and clinical course. Nishioka et al. reported a 1.3-fold increase in the incidence of FT1D within 180 days after influenza infection (7). When a patient is infected with the influenza virus, several pathogen recognition receptors including the TLR-7 recognize the single binding RNA of the influenza virus. The recognition of the virus by dendritic cells through TLR-7 results in the activation of cytotoxic T cells (8). With a strongly activated immune system, TLR-7 recognizes not only the single binding RNA of the virus but also could recognize human own cells as the target for attack. Therefore, cytotoxic T cells destroy the pancreas, and FT1D can occur after viral infections.

There was only one report in which FT1D after influenza split vaccination was described. In this report, FT1D was developed 7 days after the vaccination and combined with thrombocytopenia and lymphopenia (9). However, a clear mechanism of FT1D in this case was not proven.

Koyama et al. showed that inactive split vaccine does not directly activate cellular immunity through TLR-7 in mice (10). This is because the TLR-7 ligand is lost during the production process. Therefore, split influenza vaccination alone is unlikely to cause FT1D through the TLR-7 pathway. However, our patient has a history of influenza infections. After the influenza virus infection, parts of activated cytotoxic T cells differentiate into memory CD8-positive T cells (11). At the time of the next influenza infection or vaccination, these CD8-positive memory T cells can re-differentiate into cytotoxic T cells and initiate the immune response. In this patient, redifferentiation into cytotoxic T cells after the influenza split vaccination could destroy the pancreas and induce FT1D.

We also examined the involvement of humoral immunity. Four known antibodies were all negative. Moldoneanu et al. reported that a raise in serum IgG level was seen after 13 days from the vaccination (12). In our case, the symptoms related to diabetes were seen after 7 days from the vaccination. If the destruction of the pancreas was caused by humoral immunity, this onset time is considered too early. The serum albumin to globulin ratio reflects the activation of humoral immunity. In our case, the serum albumin to globulin ratio was unchanged between vaccination and 6 months. These findings indicated that it is unlikely that humoral immunity was associated with the destruction of the pancreas.

We described a case of FT1D developed after influenza split vaccination. Considering the results of previous studies, the redifferentiation of memory CD8-positive T cells into cytotoxic T cells is the most likely mechanism of pathogenesis. Influenza vaccination is widespread and commonly used in daily practice. It is important to accumulate case reports to clarify the mechanism and frequency of FT1D after the influenza vaccination.

Declaration of interest

The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Patient consent

Written informed consent for publication of clinical details was obtained from the patient.

Patient’s perspective

I was very worried because after the influenza vaccine was administered, I began to have severe physical discomfort, which gradually worsened. I know that side effects are an inevitable part of medical treatment, but I think there are others like me, so I hope that I can be of some help to medicine by sharing information.

Author contribution statement

TS was the attending physician of this patient. AO, KS, and YT worked with the attending physician to provide medical care for this patient during his hospitalization. TS wrote the manuscript. SK supervised manuscript writing. DA, MK, and TY were medical advisers of the Endocrine and Diabetes Unit of Kanazawa University Hospital. All authors have read and agreed to the published version of the manuscript.

References

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    Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, et al.Report of the Committee of the Japan Diabetes Society on the Research of Fulminant and Acute-onset type 1 diabetes mellitus: new diagnostic criteria of fulminant type 1 diabetes mellitus (2012). Journal of Diabetes Investigation 2012 3 536539. (https://doi.org/10.1111/jdi.12024)

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  • 2

    Hosokawa Y, Hanafusa T, & Imagawa A. Pathogenesis of fulminant type 1 diabetes: gene, viruses, and the immune mechanism, and usefulness of patient-derived induced pluripotent stem cells for future research. Journal of Diabetes Investigation 2019 10 11581164. (https://doi.org/10.1111/jdi.13091)

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  • 3

    Hanafusa T. Fulminant type 1 deabetes: 20 years of discovery and development. Diabetology International 2020 310314. (https://doi.org/10.1007/s13340-020-00458-2)

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  • 4

    Shibasaki S, Imagawa A, Tauriainen S, Iino M, Oikarinen M, Abiru H, Tamaki K, Seino H, Nishi K, Takase I, et al.Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocrine Journal 2010 57 211219. (https://doi.org/10.1507/endocrj.k09e-291)

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  • 5

    Chujo D, Kawabe A, Matsushita M, Tsutsumi C, Haseda F, Imagawa A, Hanafusa T, Ueki K, Kajio H, Yagi K, et al.Fulminant type 1 diabetes patients display high frequencies of IGRP-specific type 1 CD8+ T cells. Clinical Immunology 2021 233 108893. (https://doi.org/10.1016/j.clim.2021.108893)

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  • 6

    Sano H, Terasaki J, Tsutsumi C, Imagawa A, & Hanafusa T. A case of fulminant type 1 diabetes mellitus after influenza B infection. Diabetes Research and Clinical Practice 2008 79 e8e9. (https://doi.org/10.1016/j.diabres.2007.10.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Nishioka Y, Noda T, Okada S, Myojin T, Kubi S, Higashino T, Nakajima H, Sugiyama T, Ishii H, & Imamura T. Association between influenza and the incidence rate of new-onset type 1 diabetes in Japan. Journal of Diabetes Investigation 2021 12 17971804. (https://doi.org/10.1111/jdi.13540)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, & Flavell RA. Recognition of single-stranded RNA viruses by toll-like receptor 7. PNAS 2004 101 55985603. (https://doi.org/10.1073/pnas.0400937101)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Yasuda H, Nagata M, Moriyama H, Kobayashi H, Akisaki T, Ueda H, Hara K, & Yokono K. Development of fulminant Type 1 diabetes with thrombocytopenia after influenza vaccination: a case report. Diabetic Medicine 2012 29 8889. (https://doi.org/10.1111/j.1464-5491.2011.03391.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Koyama S, Aoshi T, Tanimoto T, Kumagau Y, Kobiyama K, Tougan T, sakurai K, Coban C, Horii T, Akira S, & Ishii K. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Science Translational Medicine 2010 2 25ra24. (https://doi.org/10.1126/scitranslmed.3000759)

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    • Search Google Scholar
    • Export Citation
  • 11

    Gerritsen B, & Pandit A. The memory of killer T cell: model of CD8(+) T cell differentiation. Immunology and Cell Biology 2016 94 236241. (https://doi.org/10.1038/icb.2015.118)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Moldoveanu Z, Clements ML, Prince SJ, Murphy BR, & Mestecky J. Human immune responses to influenza virus vaccines administered by systemic or mucosal routes. Vaccine 1995 13 10061012. (https://doi.org/10.1016/0264-410x(9500016-t)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • 1

    Imagawa A, Hanafusa T, Awata T, Ikegami H, Uchigata Y, Osawa H, Kawasaki E, Kawabata Y, Kobayashi T, Shimada A, et al.Report of the Committee of the Japan Diabetes Society on the Research of Fulminant and Acute-onset type 1 diabetes mellitus: new diagnostic criteria of fulminant type 1 diabetes mellitus (2012). Journal of Diabetes Investigation 2012 3 536539. (https://doi.org/10.1111/jdi.12024)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Hosokawa Y, Hanafusa T, & Imagawa A. Pathogenesis of fulminant type 1 diabetes: gene, viruses, and the immune mechanism, and usefulness of patient-derived induced pluripotent stem cells for future research. Journal of Diabetes Investigation 2019 10 11581164. (https://doi.org/10.1111/jdi.13091)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hanafusa T. Fulminant type 1 deabetes: 20 years of discovery and development. Diabetology International 2020 310314. (https://doi.org/10.1007/s13340-020-00458-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Shibasaki S, Imagawa A, Tauriainen S, Iino M, Oikarinen M, Abiru H, Tamaki K, Seino H, Nishi K, Takase I, et al.Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocrine Journal 2010 57 211219. (https://doi.org/10.1507/endocrj.k09e-291)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    Chujo D, Kawabe A, Matsushita M, Tsutsumi C, Haseda F, Imagawa A, Hanafusa T, Ueki K, Kajio H, Yagi K, et al.Fulminant type 1 diabetes patients display high frequencies of IGRP-specific type 1 CD8+ T cells. Clinical Immunology 2021 233 108893. (https://doi.org/10.1016/j.clim.2021.108893)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Sano H, Terasaki J, Tsutsumi C, Imagawa A, & Hanafusa T. A case of fulminant type 1 diabetes mellitus after influenza B infection. Diabetes Research and Clinical Practice 2008 79 e8e9. (https://doi.org/10.1016/j.diabres.2007.10.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Nishioka Y, Noda T, Okada S, Myojin T, Kubi S, Higashino T, Nakajima H, Sugiyama T, Ishii H, & Imamura T. Association between influenza and the incidence rate of new-onset type 1 diabetes in Japan. Journal of Diabetes Investigation 2021 12 17971804. (https://doi.org/10.1111/jdi.13540)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, Iwasaki A, & Flavell RA. Recognition of single-stranded RNA viruses by toll-like receptor 7. PNAS 2004 101 55985603. (https://doi.org/10.1073/pnas.0400937101)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Yasuda H, Nagata M, Moriyama H, Kobayashi H, Akisaki T, Ueda H, Hara K, & Yokono K. Development of fulminant Type 1 diabetes with thrombocytopenia after influenza vaccination: a case report. Diabetic Medicine 2012 29 8889. (https://doi.org/10.1111/j.1464-5491.2011.03391.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Koyama S, Aoshi T, Tanimoto T, Kumagau Y, Kobiyama K, Tougan T, sakurai K, Coban C, Horii T, Akira S, & Ishii K. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Science Translational Medicine 2010 2 25ra24. (https://doi.org/10.1126/scitranslmed.3000759)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Gerritsen B, & Pandit A. The memory of killer T cell: model of CD8(+) T cell differentiation. Immunology and Cell Biology 2016 94 236241. (https://doi.org/10.1038/icb.2015.118)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Moldoveanu Z, Clements ML, Prince SJ, Murphy BR, & Mestecky J. Human immune responses to influenza virus vaccines administered by systemic or mucosal routes. Vaccine 1995 13 10061012. (https://doi.org/10.1016/0264-410x(9500016-t)

    • PubMed
    • Search Google Scholar
    • Export Citation